The search for ideal agent(s) in the armamentarium of cancer chemoprevention continues. Agents capable to intervene at more than one critical pathway in the carcinogenic process will have selective advantage over other single-target agents. Based on the impressive array of structures and activities plant-based polyphenols are showing promise as cancer chemopreventive and often as cancer therapeutic agents. Based on our recent exciting preliminary data and published studies there is a strong possibility that oleandrin, derived from the leaves of Nerium oleander may be developed as a novel chemopreventive agent. Because of the established role of ornithine decarboxylase (ODC) in tumor promotion and nuclear factor kappa B (NF-kB), in regulating the transcription of a variety of genes involved during the promotion stage of cancer these two are important targets to block tumor promotion phase of the carcinogenesis process. The central hypothesis to be tested in this proposal is that oleandrin will afford protection against the development and progression of skin tumorigenesis by 12-O-tetradecanoylphorbol-13-acetate (TPA) application in 7, 12-dimethybenz(a)anthracene (DMBA)-initiated mouse skin by blocking ODC induction and by reducing NF-kB activation. Under the proposed specific aims we will investigate the (i) effect of oleandrin treatment on TPA-caused activation of NF-kB pathway in SENCAR mouse skin, (ii) effect of topical application of oleandrin on DMBA-initiated, TPA-promoted skin tumorigenesis in SENCAR mouse, and (iii) establish if the anti-tumor promoting effects of oleandrin are mediated via inhibition of ODC induction by employing K6/0DC overexpressing transgenic mice, which develops skin tumors following tumor initiation (by DMBA), without the need of any exogenous promotion protocol. Successful completion of this proposal will lay the foundation for an extended program to develop oleandrin as future promising cancer chemopreventive and/or therapeutic agent in humans.